JP2007510662A5

JP2007510662A5 -

Info

Publication number: JP2007510662A5
Application number: JP2006538496A
Authority: JP
Filing date: 2004-11-04
Publication date: 2007-11-29

Claims

Formula (1)

Wherein R ¹ is H, C ₁ -C ₁₀ alkyl, aryl, aryl (C ₁ -C ₆ alkyl), heteroaryl, heteroaryl (C ₁ -C ₆ alkyl), cycloalkyl, cycloalkyl (C ₁ -C ₆ alkyl), heterocyclyl, heterocyclyl _(C 1 -C ₆ _{alkyl), (C} 1 -C ₆ alkyl) -K- _(C 0 -C ₆ alkyl), aryl _(C 0 -C ₆ alkyl) -K -(C ₀ -C ₆ alkyl), heteroaryl (C ₀ -C ₆ alkyl) -K- (C ₀ -C ₆ alkyl), cycloalkyl (C ₀ -C ₆ alkyl) -K- (C ₀ -C ₆ alkyl) or heterocyclyl (C ₀ -C ₆ alkyl) -K— (C ₀ -C ₆ alkyl); wherein R ¹ is one or both of R ² and R ³ and the bond Together with the carbon to form a heterocyclyl or heteroaryl ring structure; where K is O, S, SO, SO ₂ , N (R ⁵ ) C (O), C (O) N ( ^{R 5), OC (O)} , C (O) O, be a CR 5 = CR ⁵ or C [identical to] C; wherein each alkyl has at least one independently _halo, C 1 -C ₆ alkyl, acetyl , SO ₂ R ⁶ , OR ⁶ , CO ₂ R ⁶ ; wherein each aryl, heteroaryl, cycloalkyl or heterocyclyl is independently aryl, aryloxy, C ₁ -C ₆ alkyl, Halo, OR ⁶ , SO ₂ R ⁶ , CF ₃ , OCF ₃ , NO ₂ , N (R ⁵ ) ₂ , N (R ⁵ ) C (O) (R ⁵ ), C (O) OR ⁶ , OC (O ^{^{) R 5, C (O)}} N (R 5) 2, SO 2 ^(R _{5) 2} or ^{_{N (R 5) SO 2 (}} R 5) and can be substituted;
R ² is SO ₂ R ⁸ ; where R ² can be taken together with one or both of R ¹ and R ³ and the nitrogen to which it is attached to form a heterocyclyl or heteroaryl ring structure. ;
R ³ is H, C ₁ -C ₆ alkyl, acetyl or aryl (C ₁ -C ₆ alkyl), wherein aryl can optionally be substituted with R ⁶ or OR ⁶ ; ³ can be combined with one or both of R ¹ and R ² and the nitrogen to which it is attached to form a heterocyclyl or heteroaryl ring structure;
Each R ⁴ is independently halo, C ₁ -C ₆ alkyl, alkoxy, CN, N (R ⁶ ) ₂ , acetyl, CF ₃ or OCF ₃ , OCH ₂ CF ₃ ;
Each R ⁵ is independently H, C ₁ -C ₆ alkyl, acetyl, cycloalkyl, aryl, aryl (C ₁ -C ₆ alkyl), heteroaryl or heteroaryl (C ₁ -C ₆ alkyl); Each of them is substituted with one or more R ⁴ ;
Each R ⁶ is independently H or C ₁ -C ₆ alkyl;
Each R ⁸ is independently cycloalkyl, cycloalkyl (C ₁ -C ₆ alkyl), heterocyclyl, heterocyclyl (C ₁ -C ₆ alkyl), aryl, aryl (C ₁ -C ₆ alkyl), heteroaryl, hetero Aryl (C ₁ -C ₆ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl; each of them is independently R ⁹ , halo, C ₁ -C ₆ alkyl, OR ⁵ , CN, NO ₂ , N (R ⁵ ) ₂ , C (O) R ⁵ , C (O) OR ⁵ , OC (O) R ⁵ , N (R ⁵ ) C (O) R ⁵ , N (R ⁵ ) C (O) OR ⁵ , C (O) N (R ⁵ ) ₂ , SR ⁵ , SO ₂ R ⁵ , S (O) R ⁵ or SO ₂ N (R ⁵ ) ₂ And;
X is CHC (O) OR ⁹ , CHC (O) R ⁹ , CHC (O) N (R ⁹ ) ₂ , NSO ₂ R ⁹ , CHN (R ⁹ ) ₂ , CO, CHN (R ⁹ ) SO ₂ R ⁹ , CHCH ₂ OR ⁹ , CHR ⁹ , NR ⁹ , NC (O) R ⁹ , NC (O) OR ⁹ , NC (O) NR ³ R ⁹ , or when combined with Y, CR ⁹ = CR ⁹ ;
Y is (CH ₂ ) _p , CHC ₁ -C ₈ alkyl, O, CO, or when combined with X, CR ⁹ = CR ⁹ where Y is O X is C;
Each R ⁹ is independently H, C ₁ -C ₆ alkyl, aryl (C ₁ -C ₆ ) alkyl, cycloalkyl (C ₀ -C ₆ ) alkyl, heterocyclyl (C ₀ -C ₆ ) alkyl, aryl ( C ₀ -C ₆ ) alkyl or heteroaryl (C ₀ -C ₆ ) alkyl; each of them can be independently substituted with one or more R ¹⁰ ;
Each R ¹⁰ is independently H, C ₁ -C ₆ alkyl, aryl (C ₁ -C ₆ ) alkyl, cycloalkyl (C ₀ -C ₆ ) alkyl, heterocyclyl (C ₀ -C ₆ ) alkyl, aryl ( C ₀ -C ₆ ) alkyl or heteroaryl (C ₀ -C ₆ ) alkyl, halo, OR ⁵ , NR ⁴ SO ₂ R ⁵ , N (R ⁵ ) ₂ , CN, C (O) OR ⁵ , OC (O ) be a ^{^{_{_{R 5, COR 5, NO 2}}}} , SO 2 N (R 5) 2, SO 2 R 5, S (O) R 5, SR 5, CF 3, CH 2 CF 3 or OCF _3;
Cy is aryl or heteroaryl;
m is 0-6;
n is 0, 1 or 2; and p is 1, 2 or 3;
Wherein R ⁸ is not dichlorophenyl when R ¹ is benzyloxy) or a pharmaceutically acceptable salt thereof.

R ¹ is aryl, aryl (C ₁ -C ₆ alkyl), heteroaryl (C ₁ -C ₆ alkyl), heteroaryl, aryl (C ₀ -C ₆ alkyl) -K- (C ₁ -C ₆ alkyl) Or heteroaryl (C ₀ -C ₆ alkyl) -K— (C ₀ -C ₆ alkyl); wherein K is O, N or S; wherein each alkyl is independently at least 1 Can be substituted with two halo, C ₁ -C ₆ alkyl, acetyl, SO ₂ R ⁶ , OR ⁶ , CO ₂ R ⁶ ; and wherein each aryl, heteroaryl, cycloalkyl or heterocyclyl is independently aryl , Aryloxy, C ₁ -C ₆ alkyl, halo, OR ⁶ , SO ₂ R ⁶ , CF ₃ , OCF ₃ , NO ₂ , N (R ⁵ ) ₂ , N (R ⁵ ) C (O) (R ⁵ ) , C ^O) can be replaced with ^{^{OR 6, OC (O) R}} 5, C (O) N (R 5) 2, SO 2 N (R 5) 2 or ^{_{N (R 5) SO 2 (}} R 5), The compound of claim 1.

The compound of claim 2, wherein R ¹ is aryl (C ₀ -C ₆ alkyl) -K- (C ₁ -C ₆ alkyl).

4. A compound according to claim 3, wherein R < ¹ > is benzyloxy.

The compound of claim 2, wherein R ¹ is aryl (C ₁ -C ₆ alkyl).

6. A compound according to claim 5, wherein R < ¹ > is benzyl.

R ⁸ is a ^{R 9} or ^N _C 1 -C ₆ alkyl substituted with ^(R _{5) 2,} The compound according to claim 1.

R ⁹ is heterocyclyl, A compound according to claim 7.

^9. A compound according to claim 8, wherein R9 is a nitrogen-containing heterocyclyl.

It said nitrogen containing heterocyclyl is substituted with C ₁ -C ₄ alkyl, A compound according to claim 9.

^9. A compound according to claim 8, wherein R9 is pyrrolidyl, piperidyl, piperidinyl or morpholinyl.

R ⁸ is substituted with ^{N (R} _{5) 2,} and each ^{R 5} is independently H or _C 1 -C ₆ alkyl, A compound according to claim 7.

Each R ⁵ is, H are independently methyl, ethyl, isopropyl or t- butyl, compound of claim 12.

N (R ⁵ ) ₂ is

14. A compound according to claim 13, selected from the group consisting of:

10. The compound of claim 9, wherein the nitrogen containing heterocyclyl is a bridged heterocyclyl.

The compound of claim 1, wherein R ₈ is C ₂ or C ₃ alkyl substituted with R ⁹ or N (R ⁵ ) ₂ .

N (R ⁵ ) ₂ is

17. A compound according to claim 16 selected from the group consisting of:

X and Y are ^CR 9 = CR ⁹ together compounds of claim 1.

The compound of claim 1, wherein Cy is phenyl.

The compound of claim 1, wherein X is NSO ₂ R ⁹ and Y is CH ₂ .

The compound of claim 1, wherein X is NSO ₂ CH ₃ , Y is CH ₂ , Cy is phenyl, m is 0, and n is 1.

X and Y are ^CR 9 = CR ⁹ together, Cy is phenyl, m is 0 and n is 1 The compound of claim 1.

The compound of claim 1, wherein R ³ is H or methyl.

R ¹ is aryl (C ₀ -C ₆ alkyl) -K— (C ₁ -C ₆ alkyl), aryl (C ₁ -C ₆ alkyl) or heteroaryl;
R ² is C ₁ -C ₆ alkyl in which R ⁸ is substituted with R ⁹ or N (R ⁵ ) ₂ ;
R ³ is H or Me;
X is NSO ₂ CH ₃ or, together with Y, CR ⁹ = CR ⁹ ;
Y is CH ₂ or, together with x, CR ⁹ = CR ⁹ ;
The compound of claim 1, wherein Cy is phenyl; and n is 1.

R ₈ is an ^{R 9} or ^{N (R} _{5) 2} and substituted _{C 2} or _{C 3} alkyl, A compound according to claim 24.

R ⁸ is substituted with a nitrogen-containing heterocyclyl, or

26. The compound of claim 25, substituted with a substituent selected from the group consisting of:

R ¹ is benzyloxy or benzyl A compound according to claim 24.

25. The compound of claim 24, wherein m is 0.

R ¹ is benzyloxy;
R ⁸ is C ₁ -C ₆ alkyl substituted with R ⁹ or N (R ⁵ ) ₂ ;
R ³ is H or Me;
X is NSO ₂ CH ₃ or, together with Y, CR ⁹ = CR ⁹ ;
Y is CH ₂ or, together with x, CR ⁹ = CR ⁹ ;
The compound of claim 1, wherein Cy is phenyl; and n is 1.

R ¹ is aryl (C ₀ -C ₆ alkyl) -K— (C ₁ -C ₆ alkyl), aryl (C ₁ -C ₆ alkyl) or heteroaryl;
R ⁸ is heterocyclyl or C ₂ -C ₃ alkyl substituted with N (R ⁵ ) ₂ ;
R ³ is H or Me;
X is NSO ₂ CH ₃ or, together with Y, CR ⁹ = CR ⁹ ;
Y is CH ₂ or, together with x, CR ⁹ = CR ⁹ ;
The compound of claim 1, wherein Cy is phenyl; and n is 1.

R ⁸ is, ^{N (R} _{5) 2} or a nitrogen containing heterocyclyl is substituted, the compounds of claim 30.

N (R ⁵ ) ₂ is

32. The compound of claim 31, wherein the compound is selected from the group consisting of:

R ¹ is aryl (C ₀ -C ₆ alkyl) -K— (C ₁ -C ₆ alkyl), aryl (C ₁ -C ₆ alkyl) or heteroaryl;
R ⁸ is C ₁ -C ₆ alkyl substituted with R ⁹ or N (R ⁵ ) ₂ ;
R ³ is H or Me;
X is NSO ₂ CH ₃ ;
Y is CH ₂ ;
The compound of claim 1, wherein Cy is phenyl; and n is 1.

R ¹ is aryl (C ₀ -C ₆ alkyl) -K— (C ₁ -C ₆ alkyl), aryl (C ₁ -C ₆ alkyl) or heteroaryl;
R ⁸ is C ₁ -C ₆ alkyl substituted with R ⁹ or N (R ⁵ ) ₂ ;
R ³ is H or Me;
X and Y together CR ⁹ = CR ⁹ :
Cy is phenyl;
The compound of claim 1, wherein R ⁹ is H; and n is 1.

R ¹ is aryl (C ₀ -C ₆ alkyl) -K— (C ₁ -C ₆ alkyl), aryl (C ₁ -C ₆ alkyl) or heteroaryl;
R ⁸ is heterocyclyl or C ₂ -C ₃ alkyl substituted with N (R ⁵ ) ₂ ;
R ³ is H or Me;
X is NSO ₂ CH ₃ or, together with Y, CR ⁹ = CR ⁹ ;
Y is CH ₂ or, together with x, CR ⁹ = CR ⁹ ;
Cy is phenyl;
The compound of claim 1, wherein m is 0; and n is 1.

A composition for treating obesity in a subject, said composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof .

A composition for treating diabetes in a subject, the composition comprises a compound or a pharmaceutically acceptable salt thereof of formula (I), composition.

38. The composition of claim 37, wherein the diabetes is type I diabetes.

38. The composition of claim 37, wherein the diabetes is type II diabetes.

38. The composition of claim 37, wherein the subject is identified as being at risk for diabetes.

38. The composition of claim 37, wherein the subject is identified as being at risk for diabetes by having impaired glucose tolerance.

38. The composition of claim 37, wherein the subject is identified as at risk for diabetes by having fasting hyperglycemia.

A composition for treating metabolic syndrome in a subject, said composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof .

44. The composition of claim 43, wherein the subject has atherogenic dyslipidemia.

44. The composition of claim 43, wherein the subject is obese.